Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

Mutations in GANAB, Encoding the Glucosidase IIalpha Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease.

Authors: Porath, B  Gainullin, VG  Cornec-Le Gall, E  Dillinger, EK  Heyer, CM  Hopp, K  Edwards, ME  Madsen, CD  Mauritz, SR  Banks, CJ  Baheti, S  Reddy, B  Herrero, JI  Banales, JM  Hogan, MC  Tasic, V  Watnick, TJ  Chapman, AB  Vigneau, C  Lavainne, F  Audrezet, MP  Ferec, C  Le Meur, Y  Torres, VE  Harris, PC    Harris, PC 
Citation: Porath B, etal., Am J Hum Genet. 2016 Jun 2;98(6):1193-207. doi: 10.1016/j.ajhg.2016.05.004.
Pubmed: (View Article at PubMed) PMID:27259053
DOI: Full-text: DOI:10.1016/j.ajhg.2016.05.004

Autosomal-dominant polycystic kidney disease (ADPKD) is a common, progressive, adult-onset disease that is an important cause of end-stage renal disease (ESRD), which requires transplantation or dialysis. Mutations in PKD1 or PKD2 ( approximately 85% and approximately 15% of resolved cases, respectively) are the known causes of ADPKD. Extrarenal manifestations include an increased level of intracranial aneurysms and polycystic liver disease (PLD), which can be severe and associated with significant morbidity. Autosomal-dominant PLD (ADPLD) with no or very few renal cysts is a separate disorder caused by PRKCSH, SEC63, or LRP5 mutations. After screening, 7%-10% of ADPKD-affected and approximately 50% of ADPLD-affected families were genetically unresolved (GUR), suggesting further genetic heterogeneity of both disorders. Whole-exome sequencing of six GUR ADPKD-affected families identified one with a missense mutation in GANAB, encoding glucosidase II subunit alpha (GIIalpha). Because PRKCSH encodes GIIbeta, GANAB is a strong ADPKD and ADPLD candidate gene. Sanger screening of 321 additional GUR families identified eight further likely mutations (six truncating), and a total of 20 affected individuals were identified in seven ADPKD- and two ADPLD-affected families. The phenotype was mild PKD and variable, including severe, PLD. Analysis of GANAB-null cells showed an absolute requirement of GIIalpha for maturation and surface and ciliary localization of the ADPKD proteins (PC1 and PC2), and reduced mature PC1 was seen in GANAB(+/-) cells. PC1 surface localization in GANAB(-/-) cells was rescued by wild-type, but not mutant, GIIalpha. Overall, we show that GANAB mutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation.


Disease Annotations
Objects Annotated

Additional Information

RGD Object Information
RGD ID: 11352639
Created: 2016-07-13
Species: All species
Last Modified: 2016-07-13
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.